Osteoarthritis is the commonest form of arthritis and is detectable radiologically in 80% of individuals over the age of 55 in Western populations. Symptomatic osteoarthritis of the knee, that is pain with radiographic abnormalities, is present in about 6% of individuals over the age of 30 in both the USA and the UK. In the USA approximately 21 million people have physician diagnosed osteoarthritis, most of whom have significant pain and disability. Indeed, in some 12% of all subjects with limitation of activity, the cause is osteoarthritis, and it accounts for more dependency in walking and stair climbing than any other disease. The estimated annual cost of osteoarthritis in the USA is $15.5 billion in 1994 dollars, which approaches 1% of the GNP, with more than 50% of the costs due to work loss. The problem is inevitably becoming more severe with an ageing population and the clear age related incidence of osteoarthritis (1).
The pathology of osteoarthritis comprises loss of articular cartilage and complex processes of repair with fibrocartilage and reactive bone formation, leading to disruption of normal joint and peri-articular architecture. This is associated with pain, synovial effusions and loss of function.
Traditional treatments are: weight loss, exercise and psychosocial support; simple analgesics; non-steroidal anti-inflammatory drugs; intra-articular corticosteroids; hyaluronic acid; joint lavage; physical aids and appliances. However these conservative approaches are inadequate in a significant proportion of patients for whom surgery then becomes appropriate, including synovectomy, repair of meniscal tears, realignment osteotomy, and eventually total joint replacement. Only the latter is a cure for osteoarthritis, and obviously it is only applicable to some joints and some individuals.
Other experimental and less well validated therapeutic approaches include administration of glucosamine and chrondroitin sulphate, ostensibly to promote survival or even repair of damaged cartilage, and tetracycline, interleukin-1 antagonists and inhibitors of collagenase and other matrix proteinases.
There is thus clearly an enormous need for new medications that can modify progression of osteoarthritis, and, importantly, alleviate its distressing and incapacitating symptoms of pain, joint deformity and effusions, limitation of activity and disability.
Serum amyloid P component (SAP) is a member of the conserved and evolutionarily ancient pentraxin family (2) of plasma proteins, the other member of which is C-reactive protein (CRP) the classical acute phase protein (3). Homologous proteins that share the same 3D fold (4,5), oligomeric assembly and capacity for calcium-dependent ligand binding, are present in all vertebrates (6) and even in the horseshoe crab, Limulus polyphemus (7), that is separated in evolution from primates by about 600 million years. No deficiency or protein polymorphism of SAP have been described yet in humans, and its carbohydrate component is the most invariant of any known glycoprotein (8). This is all compelling evidence that SAP has beneficial functions that contribute to survival.
However, SAP derives its name from the fact that it is universally present in the pathological tissue deposits of amyloid in the disease state of amyloidosis (9). The bulk of these deposits consists of amyloid fibrils composed of autologous protein misfolded and aggregated with a pathognomonic cross-β fold (10), together with tightly bound glycosaminoglycans of heparan sulphate and dermatan sulphate types (11). SAP undergoes specific calcium-dependent binding to these fibrils, both in vitro (12) and in vivo (13,14), and this property has been exploited to develop radiolabelled SAP as a highly specific, sensitive and quantitative in vivo scintigraphic tracer for diagnosis and monitoring of the deposits in systemic and local extra-cerebral amyloidosis (15).
One of the forms of local extra-cerebral amyloidosis that is of the greatest clinical importance is dialysis associated amyloidosis, a very serious, painful and crippling complication of long term dialysis for end stage renal failure. This type of amyloid is largely confined to joints and peri-articular structures, producing nerve compression, and bone cysts leading to disruption of joints and pathological fractures. Dialysis amyloidosis has been studied extensively using radiolabelled SAP, showing that uptake in and around joints is specific for histologically proven amyloid deposits in these locations (16,17).
Drugs which are bound by SAP have been developed for the purpose of treating amyloidosis, including Alzheimer's disease. WO95/05394 describes therapeutic and diagnostic agents for amyloidosis which comprise molecules that inhibit the binding of SAP to amyloid fibrils. EP-A-0915088 describes D-prolines and derivatives thereof for use in the treatment or prevention of central and systemic amyloidosis including Alzheimer's disease, and maturity onset diabetes mellitus. WO03/013508 describes therapeutic agents for depletion of unwanted protein populations from plasma in which bifunctional agents form a complex with a plurality of proteins to deplete them from the plasma of a subject. It is disclosed that R-1-[6-R-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]pyrrolidine-2-carboxylic acid specifically targets SAP in vivo to cause aggregation of native pentameric SAP molecules into decameric SAP-drug complexes that are then swiftly cleared by the liver.